Regulatory Challenges in the Cell Preparation Facility Adrian

Regulatory Challenges in the Cell Preparation Facility Adrian Gee Center for Cell & Gene Therapy

Overview • Regulation of Cell Therapy products • Current regulatory strategy • Critical issues for regulatory compliance by Cell Preparation Facilities • Required reporting • Resources

Background • FDA classifies Cell Preparation Facilities as drug manufacturers • FDA required to ensure that drugs are safe and effective • Initially applied existing drug regulations to cell therapy product manufacturing – products are Investigational New Drugs – manufacturing to comply with Good Manufacturing Practices (GMP)

New Approaches • Left “traditional” cell therapies unregulated – Bone Marrow Transplants – Peripheral Blood Progenitor Cell Transplants • Resulted in new regulations in 2005 • Intended to address risk of communicable disease transmission • Required manufacturing according to Good Tissue Practices

GMP or GTP? • Regulations are NOT mutually exclusive • Primary regulatory strategy based on perceived risk: – to donor – to product during manufacturing • degree of ex vivo manipulation – to recipient • Most cell therapy products must be manufactured under GMP regulations

Regulatory Strategy • Donor of cells assessed for eligibility – infectious disease testing – risk behavior assessment – not required for autologous products – use of ineligible donors acceptable under Urgent Medical Need provision • Manufacture using a controlled, reproducible and auditable process

Critical Areas • • • Standard Operating Procedures Facility issues Training Quality Product Handling & Processing Product Release & Administration

Critical Areas • Standard Operating Procedures – All aspects of operations: SOP for SOPs – Appropriate document control • record of SOP release & implementation • staff review and training • updated annually • archived appropriately

Critical Areas • Facility – annual FDA registration – environmental control – environmental monitoring – equipment: qualification, calibration, cleaning, maintenance – maintenance

Critical Areas • Facility – supplies • • selection release specifications, testing, management vendor audits (visits or questionnaire) water quality – cleaning, maintenance – waste management – pest control

Critical Areas • Training – job description – qualifications – initial training – annual retraining – annual training in GMP/GTP – assessment of aseptic technique – competency and proficiency records

Critical Areas • Quality Program – error and deviation detection & reporting – corrective actions and follow-up – dealing with positive test results postadministration – products prepared but not used – complaints from customers – audit program – annual quality report

Critical Areas • Product receipt, release and return • Product quarantine – for ineligible/pending eligibility – clearly identified area – appropriate labeling • Product storage and expiration • Product recall

Critical Areas • Process controls • Process validation – started at Phase 1 – completed before Phase 3 • Labeling and label controls – correct product name – required language: Autologous use only etc. – appropriate warnings: Reactive test for. . . etc.

Product Release • Certificate of Analysis – identity – purity – potency • • • Tests used – CFR compliant? Sensitivity of testing method Review of results Released through QA Appropriate labeling

Product Administration • • Prescription for administration Record of removal from inventory Appropriate cross-checks Record of additional manipulation and retesting • Record and investigation of adverse reactions

Required Reporting • Annual establishment registration • Annual IND report • Dear Cell/Gene Therapy letter response – all products manufactured – manufactured and not used • Response to 483’s • Documentation of SAEs

Resources • FDA website – GMP and GTP regulations • CBER website – Guidances • Validation of sterility testing • Inspections – Points to Consider – “What’s New at CBER” alerts – CBER presentations

Resources • Professional Societies – – ISCT ISSCR AABB ICCBBA • Accrediting Agencies – FACT – AABB – CAP • Professional Standards – FACT – AABB – USP • Consultants

Conclusions • Cell Preparation Facilities are under regulatory scrutiny • Regulations are still evolving – recent guidances for CMC sections & pancreatic islets • Ignorance cannot be used as an excuse • Good faith efforts are appreciated • Communication is essential

Acknowledgements CAGT Colleagues NHLBI SCCT PACT